Phenalkylamines



2,784,193 PHENALKYLAMINES Everett M. Schultz, Ambler, Pa., assignor to Merck & Co., Inc., Rahway, N. 1., a corporation of New Jersey No Drawing. Application January 19, 1955 Serial No. 482,?94

4 Claims. (Cl. 260-'-294.7)

s itchart and their acid or quaternary ammonium salts, wherein R and R -are either the same or different and are selected from hydrogen, alkyl, allzoxy or a halogen radical; R

is hydrogen-or a lower alkyl radical; A is a tertiary amino group selected from the dialkylamino or cycloaliphaticamino group, advantageously a morpholine, piperidine,

or pyrollidine radical, or the acid or qauternary amino United States Patent" I illustrated above can be formed by any of the convennium salt of either the dialkylamino or cycloaliphatic- 1 amino group; n is zero or-l; and m is the numeral 2, 3 or 4. The alkyl and a'lkoxy radicals represented by R and R are advantageously lower alkyl or lower -alkoxy, and the halogen radicals represented by R and R at advantageously bromine, chlorine or iodine. The compounds of this invention have utility as therapeutic agents, for example, as local anesthetics-or as antifibrillatory agents. Some of the compounds have a very high order of local anesthetic activity and are especially useful for this p rpose because they cause little or no irritation to the tissues to which they are applied. 3

The compounds are generally employed in the form of an acid salt or in the form of a quaternary ammonium salt. The compounds of this invention are advantageously prepared by reacting an appropriate halo ketone (I) with an appropriate alkylene diamine (II) in the presence of an inorganic baseor an excess of the alkylenedi'amine reactant (H). The inorganic base or excess alkylene diamine can, if desired, be provided in order to'bihd as .a

halide salt the hydrogen halide formed in the reaction. I

The process for preparing the novel compounds of this invention can be illustrated as follows: J

wherein X represents a halogen 'substituent, preferably the like.

- -170 (at a pressure of 1 mm. Hg). was taken up in ether and the hydrochloride salt pre- 2,784,193 Patented Mar. 5, 1957 "ice tassium carbonate.

The acid salts of the compounds of this invention are prepared by any well-known method as by suspending the diamine (III) in water and adding any desired acid to the mixture until all of the diamine goes into solution. Any acid salt of these compounds can be prepared by this method although for all practical purposes the mineral acid salts such as the hydrochloride, hydrobromine, hydroiodide, hydrogen sulfate or phosphoric acid salt and the like, or organic acid salts such as acetic acid or other relatively non-toxic organic acid salts are preferably prepared by addition of advantageously the anhydrous acid to an ether solution of the base.

The quaternary ammonium salts of the compounds tional quaternizing agents such as alkyl halides or aralkyl halides, preferably an alkyl bromide or an alkyl iodide or benzyl chloride or benzyl bromide or a substituted benzyl halide; and alkyl sulfates as methyl sulfate and I Advantageously the mineral acid saltof the diamine can' be neutralized and the free base isolated and .reacted with the desired quatermzing agent suitably in a non-aqueous medium.

As the new compounds of this invention are primarily to be used as therapeutic agents, the salts formed'should be such that they will not produce any undesirable toxic manifestations when administered.

The preparation of the compounds of this invention will be described in more detail in the following examples which are illustrative and in nowise limit the procedures by which these compounds can be prepared. All physical 35 constants are uncorrected values.

Example 1.-I-( B-diethylaminoethylmethylamino)-1,3-

diphenyl-Z-propanone dihydrochloride ether (50 ml.). The mixture was allowed to stand overnight at room temperature after which it was made basic with dilute sodium hydroxide. The mixture then was shaken and the ether layer separated and set aside. The aqueous layer was again extracted with ether and the ether layer removed. The ether solutions were combined and dried over sodium sulfate. The ether then was evaporated and the residue was distilled yielding l-(fl-diethylaminoethylmethylamino)-1,3-diphenyl-2-propanone, B. P. The distillate cipitated by the addition of dry hydrogen chloride gas. The precipitate was a gummy, yellow-red, non-crystalline solid which crystallized after standing several days at room temperature. The other then was decanted and the residue was stirred with hot acetone. The almost colorless precipitate which formed was collected by filtration, M. P. 181-183 C. when placed in bath at C.

-After two recrystallizations from a mixture of hot isopropyl alcohol and absolute ether there was obtained 7.0 grams of 1- (p diethylaminoethylmethylamino) 1,3-

-'diphenyl-2-propanone dihydrochloride, M. P. 185-186 C. Example 2.--1-(B-4-m0rpholinylethylamin0)-1,3-di-mtolyl-Lpropanone dihydrochloride By replacing the, l-bromo-1,3-diphenyl-2-propanone and the p-dicthylaminoethylmcthylamine employed in Example 1 by an equimo'lecular quantity of 1,3-di-mtolyl-Z-propanone and fl-4-morpholinylethylamine respectively, and following substantially the same procedure de' scribed in Example 1, there is obtained l-(pjgt-rnorpholinylethyalmino)-l,3-di-m-tolyl-2-propanone dihydrochloride.

Example 3.' 1- )a 1 'pyrrolidylthylm'tliylaniHi6)JB- di-o-l;roMophriyl-Z-pfobanbhe ailiydfachlria'e By replacing the l-bromo-l,3-diphenyl 2=pfopanoneand the fl-diethylaminoethylmethylamiue employed in "Example 1 by an equimolecular quantity of 1,3- di-o-bromoph'enyl-Z-propanoue and p-1-pyrrolidylethylmethylamine respectively, and following substantially the sameprocedure described in Example 1, there is obtained -1-(;3-lpyrrolidylethylmethylamino)-1,3-di o bromophenyl-Z- propanone dihydrochl'oride.

-Erample 4.- a ()S-Dietliylarriinothylmethylamino) -ocpher'tylacetophenone dihydrbchloride Desyl chloride (4.6 'g.,0'.02 mole) was nifire'rfiwithfbdiethylaminoethylmethylaniiiie 2.6 '-g., mate without'solvent and the miirtur'e was allowe'd'to'stand at 'room temperature. Considerable heat'wa's e'volved and "aele'ar orange 'sol'utio'n resulted. A'ft er "thirty 'rr'1iriiifes, 7at'er -(50 'ml.) and concentrated "hydrochloric acid 10 f'mli) were added. The insoluble oilwhich formed wa'seittfacted with'ether and discarded. The aqueoussolii'tiontli'en was made basicfandthea (fiJiiethylamindethyliriethylainind)- 'u plienylac'et'oplienone 'wast'aken in ether, washed 'tinies withwat'er and dried over sodiiim 'sulfate. The

hydrochloride salt of the bis-tertiary' aniitie"Wasiifeifipi. =ta'ted by passing in dr -hydrogen chlorine-gas. The-salt precipitated as a gum which icrystalliz'ed'aft'er lengthy rubbing under ether yielding 4.0 g. of crude d w di'etiiylaminoethylmethylamino) o phehylacetophnohe" diliydfm chloride, M. P.210'220 C. A'ftertw'o "r'ec'fYtzilliitttions from isopropyl alcohol, and an additional recrystalliza- 'tion fr'om'ethanol, 1.5 g. of purifieda-( fl dithylamintr ethylnietllylamino) -'a phenylacetdph'enone'dihydro'ciiloride was obtained, M. P. 213-215" C. (Withdeddmpfifi- 7 tion).

Example 5."a (5-4 131orpholinylbutylmethylaiizino)-a-(0- bromophenyl)-b-brmoacetophenone dihydrdchldride By replacing the desyl chloride and the fi-diethylaminoethylmethylamine employed in Example 4 by an equimolecular quantity of 0,0{dibromodesoxybenzoin and 4-mo'rph'oli'nylbutylmethylamiue respectively, and following'subs'tantiallyf the same procedure described in Example 4, there is "obtained a-(ai-morpholinylbutylmethylamino)-u-'(o-br'omo'phenyl) o bromoacetophenone dihydrochloride.

Example'ti;'-a [fl 1-piperidyl)ellzy'linethylahiiitiil 'aph'e'nylacetoplzenone dillya'rdchlar'ide Desyl-ehloride. (23.1 :g., 0.1 mole) was =mixedwith" 18- (-1 -pip eridylethy1')-In8thylamine (14.2 g., 0.1 mole) without solvent and the mixture was allowedtosta'nd. The reaction proceeded with evolution of heat yielding a clear yellow solution within five minutes. The mixture was allowed to stand an additional two hours, after which water (150 ml.) and concentrated hydrochloric acid (20 ml.) were added. The insoluble oil which formed was extracted with'etherand discarded. The aqueous'solution was made basic, and the e-[-fl-(I-PiperidyDethylmethylamino] -a-phenylacetophenone that separated was "-t alt'en up in ether, washed three times with water and dried over sodium sulfate. The hydrochloride salt was precipitated by passing dry hydrogen chloride gas into the ether solution of the amine. Thes'alt was triturat'edwith acetone, wherup'on a poorly crystalline material was ob- "tained. This crystalline material wasdis's'olvedin ainixt'ure ofis'opropyl alcohol (3001111.) and water 3 'l'nll) and precipitated by the addition of ether (lower after two-additional i'ee'rystallizati'ons frorn'faiiiixtugeef isopropyl alcohol (78 ml.) and ethanol (SStnLYtlidr'e av-canes was obtained 9.5 g. of a-[/3-(l-piperidyl)ethylmethyiamino] a-pheriylacetophen one 'dihyd'r'dchlo'ride, 'P.

207-209 C. (with decomposition). 1

Example 7.-a [fi (I-piperidyl)ethylmethylamino]-a- (p-methoxyphenyl)p methoxyacetophenone dihydrogen sulfate p,p-Methoxydesyl'chloride (1416 g., 0.05 mole), 3-(1- .piperidylcthyl)-methylamine (7.1 'g., 0.05 mole) andpotassiurn carbonate (6.9 g 0.05 mole) were mixed and allowed to stand for three hours at room temperature. The reaction proceeded "with "the: evolution of heat yielding a pasty mass. Water and -sufficient concentrated hydrochloric acid'we'r'e added'to makethe mixture acidic. The insoluble oil which formed was extracted with ether and discarded. The aqueous solution was made basic, whereupon a- [fi(l-piperidyl)ethylmethylamino] on (p- "fiitlidrypiin i)phreindayaewpnenoneseparated. The lt'ateda'fiiiiie wastake'jn up in ether "and 'dried giver seam-m sulfate, H The sulfate salt was prepared b'y' adding recip 'co hcent rated sulfuric acid to the "ether solution 'of'the fairfiuejuntil tue'mixmrewas'jus; acidic. The "sulfate' s'alt separated "as 'a' gum whichcryst'allizedwhen r'ubbe'dunder acetone. After three recrystallizations from ar'nix'tii're o'f"'thanol (150 m1.) and water (5 ml.) 't hrewasjobtained 7.7 g. of a-[fl-(1-piperidyl)ethylmethylaminol a- (p methbxyphenyl)-p-methoxyacetophenone dihydrogen sulfate, M. P. 205=206 C.

Example 8.a-(/3-Diethylamin0thylmethylamino)-aphenyl-p-methylacetophenone dihydrochloride v;- it-Bromobenzyl p-methylphenylketone (1414 g., 0.05 mole) was dissolved in ether ml.), and-potassium ca rbonate (6.9 g., 0.05 mole) was added. fl-Diethylaminoethyhnethylamine (6.5 g., 0.05 mole) was added glropwis'e over a period of ten'minutes with stirring to line precipitate was twice recrystallized from a mixture of isopropyl alcohol ml.) and water (16 ml.) yielding 7.4 g. of a -(B-diethylaminoethylmethylamino)-a-.

phenyl p-Iriethylacetophenone dihydrochloride, M. P. 227 C. (with decomposition) 9.lm [18 (I-piperidyl)ethylniethylarninol-abh'riyl-p-m ethylaeetophenbne dihydrochloride fii B'foiiiohefnzyl p methyIph'en'yl ketone 203 g., 0.07 "n1 6le)f' was dissolved in ether ml.), a'ndpotas'sium earner-m w g., 0.07 'mole) was added. ft-(l-piperid'yletIiYD-iriethyla'mine (10 'g., 0.07 mole) was added'in'portionso'ver a ten minute period with stirring. The mii't'tiire "w'asallowed 'to stand at room temperature for two hours, after which water (200 ml.) and concentrated hydrochloric acid were added to make the aqueous layer acidic. The ether layer was-separated -.anddiscarded. The aqueous layer then was made basic and the a- [fl-( 1 piperidy1)- ethylmethylamino] a phenyl p *methylacetophenone which precipitated was taken up in ether, washed with five portions of water and dried over sodium sulfate. The dihydrochloride salt of the amine was precipitated by passing hydrogen chloride gas into the 'dfied 'ether solution. Thesalt "was separated and after three recrystallizations from a mixture of ethanol (100 m1.) and ether (100 ml.) yielded 8.3 g. of a-[ 3-(l-piperidyl)ethyImethyIaminOJ-aphenyl p-methylacetdphenone dihydrochloride, M. P. 4 ""225 C, (with-decomposition).

Example o. (p-Diethylaminoerhylmethylamino) -a- (p-methoxyphenyl) p methoxyacetophenone dihydrochloride.

p,-p'-Dimethoxydesyl chloride (17.5 g., 0.06 mole), diethylaminoethylmethylamine (8.5 g., 0.06 mole) and potassium carbonate (8.3 g., 0.06 mole) were mixed and allowed to stand two hours at room temperature, after which 200 ml. of water was added and sufficient concentrated hydrochloric acid to make the solution acidic. The insoluble material which formed was extracted with ether, and the ether extract was discarded. The aqueous solution was made basic, and the a-(fl-diethylaminoethylmethylamino) a (p methoxyphenyl) p methoxyacetophenone which was liberated was taken up in ether, washed with four portions of water and dried over sodium sulfate. The dihydrochloride salt of the amine was precipitated by bubbling dry hydrogen chloride gas into the ether solution. The salt crystallized after considerable rubbing. After two recrystallizations from ethanol, 9.7 g. of a-(ddiethylaminoethylmethylamino)-u-(p-methoxyphenyl)p-methoxyacetophenone dihydrochloride was obtained, M. P. 213 C. (with decomposition).

Example 11.a-(,B-Diethylaminoethylmethylamino) aphenyl-p-chlroacet0phen0ne dihydrochloride a-Bromobenzyl p-chlorophenyl ketone (15.6 g., 0.05

mole) was dissolved in ether (100 ml.). Potassium carbonate (6.9 g., 0.05 mole) was added, and then p-diethylaminoethylmethylamine (6.5 g., 0.05 mole) was added in portions with swirling over a fifteen-minute ;period. The mixture was allowed to stand 1% hours at room temperature, during which time some heat was evolved. Water (150 ml.) was added to the mixture, and suificient concentrated hydrochloric acid was added to make the mixture acidic. The ether layer was separated and discarded. The aqueous solution was made basic, and the a-(,3-diethylaminoethylmethylamino)-aphenyl-p-chloroacetophenone which was liberated was taken up in ether and dried over potassium carbonate. The dihydrochloride salt of the amine was precipitated by bubbling dry hydrogen chloride gas into the ether solution. The salt quickly crystallized. After one recrystallization from a mixture of ethanol (75 ml.) and water (4 ml.) and an additional recrystallization from a mixture of methanol (15 ml.) and ethanol (50 ml.), 6.2 g. of a (,8 diethylaminoethylmethylamino) 0c phenylp-chloroacetophenone dihydrochloride was obtained, M. P. 218-219 C. (with decomposition).

Example 12. z (Gamma I piperidylpropylmethyl- Potassium carbonate (9.7 g., 0.07 mole) was added to a solution of a-bromobenzyl p-methylphenyl ketone (17.3 g., 0.06 mole) in ether (150 ml.). To this solution, gamma 1 piperidylpropylmethylamine (11 g., 0.066 mole) was added in portions over a fifteen-minute period. Some heat was evolved. The mixture was allowed to stand one hour, after which water (200 ml.) was added and then concentrated hydrochloric acid (25 ml.). The ether layer was separated and discarded. The aqueous layer was made basic and the a-(gamma-l-piperidylpropylmethylamino) a phenyl p methylacetophenone which separated was taken up in ether, washed five times with water and dried over sodium sulfate. The dihydrobromide salt of the amine was prepared by adding 48% aqueous hydrogen bromide to the ether solution until it became acidic. The salt precipitated as an orange oil. The ether was decanted and the residual oil dissolved in acetone (200 ml.). Ether (approximately 50 ml.) was added to incipient precipitation. The salt gradually crystallized out at room temperature. After one recrystallization from a mixture of isopropyl alcohol (40 ml.) and methanol (40 ml.), 10.5 g. of a-(gamma-l-piperidylpropylmethylamino) oz phenyl p niethylacetophenone' dihydrochloride, M. P. 225-227 C. was obtained.

Example 13.--1 (gamma 1 piperidylpropylmethylamino) 1,3 diphenyl 2 propyl propanone dihydrochloride 1 Bromo 1,3- diphenyl 2 propanone (8.7 g., 0.03 mole), gamma-1-piperidylpropylmethylamine (9.4 g., 0.06 mole), and ether ml.) were mixed and allowed to stand one hour at room temperature. Heat was evolved immediately. Water (200 ml.) and concentrated hydrochloric acid (25 ml.) were added, and the ether layer which separated was discarded. The aqueous layer was made basic and the 1-(gamma-1-piperidylpropyl-' methylamino) 1,3 diphenyl 2 propyl propanone which precipitated was taken up in ether, washed five times with water and dried over sodium sulfate. The hydrochloride salt of the amine was obtained by bubbling dry hydrogen chloride gas into the dried ether solution. The salt crystallized when rubbed with acetone. After one recrystallization from a mixture of isopropyl alcohol (30 ml.) and ether (35 ml.) and a second recrystalliza tion from a mixture of acetone (30 ml.) and ethyl alcohol (12 ml.), 5.0 g. of 1 (gamma 1 piperidylpropylmethylamino) 1,3 diphenyl 2 propylpropanone dihydrochloride, M. P. 128-131" C., was obtained.

Example I4.-cz (p Diethylaminoethylamino) ozphenyl p chloroacetophenone dihydrochloride a-Bromobenzyl p-chlorophenyl ketone (11.0 g., 0.0354 mole), p-diethylaminoethylamine (8.1 g., 0.07 mole) and ether (100 ml.) were mixed and allowed to stand one hour at room temperature. The reaction occurred very rapidly with the evolution of heat. A 5% hydrochloric acid solution ml.) then was added, and the ether layer which separated was removed and discarded. The aqueous layer was made basic, and the a-(B-diethylaminoethylamino) a phenyl p chloroacetophenone which separated was taken up in ether, washed five times with water and dried over sodium sulfate. The dihydrochloride salt of the amine was prepared by passing dry hydrogen chloride gas through the dried ether solution. The salt precipitated as a gum. The ether was decanted, and the gum was rubbed under acetone (200 ml.), whereupon it crystallized. After one recrystallization from a mixture of isopropyl alcohol (50 ml.) and water (4 ml.) and a second recrystallization from a mixture of isopropyl alcohol (20 ml.) and methanol (15 ml.), 2.4 g. of a (B diethylaminoethylamino) a phenyl pchloroacetophenone dihydrochloride was obtained, M. P. 204-207 C. (with decomposition).

Example I5.a (p Diethylaminoethylmethylamino)- a phenylacetophenone methobromide Example I6.-oc (13 Diethylaminoethylmethylamino)- a (p methoxyphenyl) p methoxyacetophenone methobromide a (p Diethylaminoethylmethylamino) -a-p-rneth0xyphenyl)-p-methoxyacetophenone dihydrochloride (4.6 g., 0.01 mole), obtained as described in Example 10, was decomposed with aqueous sodium hydroxide to form the free base. The free amine was taken up in ether, dried mew l e .w -l qu s meth l 2x9 1 u d Ah m utr Exizmble 7.1-(fl-diethylaminoethylmethylamiqg) 1,3-

diphenyl-Z -propanqne dia eetate niglelwbs, aigied." Thefsolution' was. allowed to stand m n-mama h'j' drdg en;lovi ei' alliflnbwei" lkoi'y and h'z iloge R is selected from -the group consisting of hydfogen 21nd lowei' alkyhradicals; K is a tertiary. aniino--g.roup.selec ted from the groiip 'consisting ofla lbwendialkylaminongroup and a morpholinyl, apyrrolidyl and a piperidyl groumm is. a numeral selected from zero. and one; and mv is, a numeral selectedlfrom 2-, 3- and .4.

2; m-(13-Diethylaminoethylmethylanfino) a. phenyhp: chlora-acetuphenone dihydrochloride. V

3. o ('y -1-Piperidylpmpylmethylamino) a. phenyhp: methyl-abetophenone dihydrochloxide.

4.. 1-(:y-1-I?iperidylpropylmethyla;nino)'- 1,3:dipl1cnyl:

21propanone .dihydrochloride,

No. references cited. 

1. AN ALKYLENE DIAMINE COMPOUND SELECTED FROM COMPOUNDS HAVING THE STRUTURAL FORMULA THEIR ACID SALTS AND QUATERNARY AMMONIUM SALTS, WHEREIN R1 AND R2 ARE SELECTED FROM THE GRUP CONSISTING OF HYDROGEN, LOWER ALKYL, LOWER ALKOXY AND HALOGEN RADICALS; R3 IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN AND LOWER ALKYL RADICALS; A IS A TERTIARY AMINO GROUP SELECTED FROM THE GROUP CONSISTING OF A LOWER DIALKYLAMINO GROUP AND A MORPHOLINYL, A PYRROLIDYL AND A PIPERIDYL GROUP; N IS A NUMERAL SELECTED FROM ZERO AND ONE; AND M IS A NUMERAL SELECTED FROM 2,3 AND
 4. 